title: Structure-activity study to develop cationic lipid-conjugated haloperidol derivatives as a new class of anticancer therapeutics.
abstract: Haloperidol (HP), a neuroleptic drug, shows high affinity toward σ receptors (SR). HP and reduced-HP at higher concentration were known to induce apoptosis in SR-overexpressing carcinomas and melanomas. Herein, we report the development of cationic lipid-conjugated haloperidol as a new class of anticancer therapeutics. In comparison to HP, the C-8 carbon chain analogue (HP-C8) showed significantly high, SR-assisted antiproliferative activity against cancer cells via caspase-3-mediated apoptosis and down-regulation of pAkt. Moreover, melanoma tumor aggressiveness in HP-C8-treated mice was significantly lower than that in HP-treated mice. HP-C8 simultaneously reduced Akt-protein level and increased Bax/Bcl-2 ratio in vascular endothelial cells, thereby indicating a possible protein kinase down-regulatory and apoptosis inducing role in tumor-associated vascular cells. In conclusion, we developed σ receptor-targeting cationic lipid-modified HP derivatives as a promising class of anticancer therapeutic that concurrently affects cancer and tumor environment associated angiogenic vascular cells through induction of apoptosis and Akt protein down-regulation.
authors.affiliation: Division of Lipid Science and Technology, Indian Institute of Chemical Technology, Hyderabad, Andhra Pradesh 500007, India.
authors.forename: Krishnendu
authors.initials: K
authors.lastname: Pal
authors.forename: SubrataKumar
authors.initials: S
authors.lastname: Pore
authors.forename: Sutapa
authors.initials: S
authors.lastname: Sinha
authors.forename: Rajiv
authors.initials: R
authors.lastname: Janardhanan
authors.forename: Debabrata
authors.initials: D
authors.lastname: Mukhopadhyay
authors.forename: Rajkumar
authors.initials: R
authors.lastname: Banerjee
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D019556:COS Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002522:Chlorocebus aethiops; D055808:Drug Discovery; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006220:Haloperidol / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D008055:Lipids / Q000737:chemistry*; D008297:Male; D051379:Mice; D010750:Phosphoproteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D017480:Receptors, sigma / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D008055:Lipids; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D017480:Receptors, sigma; D051057:Proto-Oncogene Proteins c-akt; D006220:Haloperidol